There is marked phenotypic variability among patients with amyotrophic lateral sclerosis (ALS) and related disorders, such as frontotemporal dementia (FTD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), and hereditary spastic paraplegia (HSP), with respect to age and site of disease onset, upper versus lower motor neuron pathology, presence and degree of cognitive dysfunction, rate of disease progression and survival from disease onset. To explore this heterogeneity, we will examine a well- characterized cohort of patients enrolled in the CReATe Consortium?s Phenotype-Genotype-Biomarker (PGB) Protocol, for whom we have collected a wealth of clinical and genomic data. We aim to identify genetic variants that modify underlying phenotypic characteristics of ALS and related diseases (age at onset, rapid versus slow disease progression, cognitive impairment, survival from onset). Our strategy will include innovative approaches (e.g., detection of retroelement insertion and viral integration) and cutting-edge technology (long- read single-molecule real-time [SMRT] sequencing) to uncover variation that has been missed thus far. Additionally, we will explore gene-environment interactions in a targeted manner by focusing on variants in protein folding and DNA repair pathways and environmental risk factors (e.g., cigarette smoking). Replication will be conducted in studies through our large collaborative network. The factors we identify through our studies will enhance our ability to decipher the basis for the phenotypic heterogeneity of this group of diseases and will be critical to the success of future clinical trials.